Study On The Conformational Polymorphic Behaviors Of Flufenamic Acid

Due to the molecular conformational flexibility,flufenamic acid(FFA)presents various crystalline structures,among which form Ⅰ and form Ⅲ are the conformational polymorphs.FFA was chosen as the model compound to investigate the impact of conformational flexibility on the formation of different polymorphs,which can provide the potential theoretical guidance for the reveal of pharmaceuticals polymorphic behavious in molecular level.In this dissertation,cooling crystallization was firstly utilized to prepare different FFA polymorphs.Morphology features,micro-stuctures and dissolution thermodynamic properties of the two FFA polymorphs were characterized via the combination of X-ray powder diffraction(PXRD),polarizing microscope(PLM),scanning electron microscope(SEM),Fourier transform infrared spectroscopy(FT-IR),Raman spectroscopy,hot-stage,thermogravimeter(TG),et al.It was found that form Ⅰ and form Ⅲ of FFA are an enantiotropic system and form Ⅰ is the stable form in high temperature conditions.In the section of the FFA crystallization thermodynamics investigation,a static method was applied to measure the solubility of FFA both in the pure solvents(i.e.water,acetonitrile and isopropanol)and the binary solvent systems(i.e.water+acetonitrile,and water+isopropanol).The solubility data were correlated with temperature and/or binary solvent compositon to estabilish the prediction models for FFA solubility(i.e.Apelblat model,CNIBS/R-K model and Jouyban-Acree model).Based on the calculation of the dissolution thermodynamic properties,it was revealed that the dissolution processes of FFA in the selected solvents are endothermic,non-spontaneous and enthalpy-driven.1H chemical shifts of FFA in acetonitrile-d3 and in acetonitrile-d3+water were extracted from NMR spectra,which explained the cosolvency phenomena of FFA in the(acetonitrile+water)binary solvent system.In-situ Raman technique was used to monitor the process of cooling crystallization of FFA and the obtained solid forms were characterized by PXRD.The impacts of temperature,supersaturation and solvent on the formation of FFA polymorphs were investigated.Potentail energy surface scanning was calculated using the GAUSSIAN 09 package,a quantum chemistry computational software.Single point energy of FFA molecules with various conformations were calculated depending on SMD implicit solvation model using a B3LYP hybrid generalized-gradient approximation fuction and a Gaussian-type 6-31G*basis set.Further FFA-solvent interaction calculation was done and mechanism of conformational change between different polymorphs was unveiled.At last,in-situ Raman technique was used to monitor the process of solvent-mediated polymorphic transformation.Thermodynamic and kinetic driving forces of the process were confirmed as well as the transformation rate controlling step.Impact of factors including temperature and solvent on the polymorphic transformation process was investigated and the mechanism of molecular conformational flexibility on the transformation process was revealed.